The role of voltage-gated and
ligand-gated ion channels in epileptogenesis of both genetic and acquired
epilepsies, and as targets in the development of new
antiepileptic drugs (AEDs) is reviewed. Voltage-gated Na+ channels are essential for action potentials, and their mutations are the substrate for generalised
epilepsy with
febrile seizures plus and
benign familial neonatal infantile seizures; Na+ channel inhibition is the primary mechanism of
carbamazepine,
phenytoin and
lamotrigine, and is a probable mechanism for many other classic and novel AEDs.
Voltage-gated K+ channels are essential in the repolarisation and hyperpolarisation that follows paroxysmal depolarisation shifts (PDSs), and their mutations are the substrate for the
benign neonatal epilepsy and
episodic ataxia type 1; they are new targets for AEDs such as
retigabine. Voltage-gated Ca2+ channels are involved in
neurotransmitter release, in the sustained depolarisation-phase of PDSs, and in the generation of absence
seizures; their mutations are a substrate for
juvenile myoclonic epilepsy and the absence-like pattern seen in some mice; the antiabsence effect of
ethosuximide is due to the inhibition of thalamic T-type Ca2+ channels. Voltage-gated Cl- channels are implicated in
GABA(A) transmission, and mutations in these channels have been described in some families with juvenile
myoclonic epilepsies,
epilepsy with grand mal
seizures on awakening or
juvenile absence epilepsy. Hyperpolarisation-activated
cation channels have been implicated in spike-wave
seizures and in hippocampal epileptiform discharges. The Cl-
ionophore of the
GABA(A) receptor is responsible for the rapid post-PDS hyperpolarisation, it has been involved in epileptogenesis both in animals and humans, and mutations in these receptors have been found in families with
juvenile myoclonic epilepsy or generalised
epilepsy with
febrile seizures plus; enhancement of
GABA(A) inhibitory transmission is the primary mechanism of
benzodiazepines and
phenobarbital and is a mechanistic approach to the development of novel AEDs such as
tiagabine or
vigabatrin. Altered
GABA(B)-receptor function is implicated in spike-wave
seizures.
Ionotropic glutamate receptors are implicated in the sustained depolarisation phase of PDS and in epileptogenesis both in animals and humans;
felbamate,
phenobarbital and
topiramate block these receptors, and attenuation of glutamatergic excitatory transmission is another new mechanistic approach. Mutations in the
nicotinic acetylcholine receptor are the substrates for the nocturnal
frontal lobe epilepsy. The knowledge of the role of the
ion channels in the
epilepsies is allowing the design of new and more specific therapeutic strategies.